Process for metabolic control and high solute clearance and solutions for use therein

ABSTRACT

The present disclosure describes novel standardized citrate replacement fluid solutions and a standardized dialysate solution for use with CRRT methods. The standardized citrate replacement fluid solutions and standardized dialysate solutions do not require modification based on the clinical status of the individual patients. The use of the standardized solutions described herein offers significant advantages over the prior art solutions used in CRRT. The present disclosure describes superior metabolic and electrolyte control and significantly increased dialyzer patency in: (a) 24 intensive care unit (ICU) patients with ARF using a 0.67% trisodium citrate replacement fluid solution, and (b) 32 ICU patients with ARF using a 0.5% trisodium citrate replacement fluid solution. Both groups were treated with Bicarbonate-25 dialysate and achieved effluent rates of 35 mL/kg/hr.

FIELD OF THE DISCLOSURE

The present disclosure relates generally to the field of renal functionand renal disease. The present disclosure relates specifically to theuse of a defined dilute regional trisodium citrate solution duringcontinuous renal replacement therapy for the treatment of renal disease.

BACKGROUND

Continuous renal replacement therapy (CRRT) is well established as amodality for the management of renal failure in the critically illpatient. When CRRT was first developed, the major indications for usewere fluid and solute removal associated with renal failure, such asthose patients developing acute renal failure (ARF). Acute renal failure(ARF) is rarely an isolated process but is often a complication ofunderlying conditions such as sepsis, trauma, and multiple-organ failurein critically ill patients. As such, concomitant clinical conditionssignificantly affect patient outcome. CRRT applications have developedover time to include use for patients with chronic renal failure (CRF)and for other indications. Continuous renal replacement therapy (CRRT)has recently emerged as the dialysis technique of choice for criticallyill patients with acute renal failure (ARF). There are several types ofCRRT therapy, including but not limited to, continuous venovenoushemofiltration (CVVH). CRRT is generally recognized as offeringsignificant advantages to intermittent dialysis for fluid and metaboliccontrol (1). Additionally, high ultrafiltration rates (greater than orequal to 35 ml/kg/hr) using CRRT, such as CVVH, have been associatedwith improved patient survival (2).

During CRRT procedures, solutions must be added to keep the bloodflowing through the CRRT device from clotting. Heparin sodium is themost common anticoagulant used for CRRT. Systems are frequently flushedwith dilute heparin through the system during the priming procedure(5,000-10,000 U/L normal saline) followed by a constant delivery ofheparin for the duration of therapy. For many years, it was theanticoagulant of choice for all forms of dialysis that used a bloodpath. However, as CRRT was applied to the more profoundly ill patients,heparin was found to be associated with complications caused bycoagulation disorders seen in the critically ill. Side effects that maybe observed include, but are not limited to, systemic anticoagulation,thrombocytopenia and suppressed aldosterone secretion. The effects onsystemic coagulation make heparin administration very problematic inpatients with gastrointestinal bleeding or traumatic injury in whichhemostasis is impaired due to coagulation factor consumption or occultbleeding from wounds or vascular puncture sites. Frequent monitoring ofcoagulation studies and platelet counts as well as continual monitoringfor bleeding complications is essential for any patient undergoingheparin anticoagulation of the CRRT system. Patients do not requirebolusing with heparin before initiation of therapy, because the goal isnot to anticoagulate patients but rather to provide regionalanticoagulation for the system. If the heparin used for priming is notthoroughly flushed from the system, patients will still receive a smallheparin bolus from the priming volume.

Trisodium citrate has been used for many years as an anticoagulant forblood products. It was introduced to CRRT as a regional anticoagulant inthe early 1990s. Relatively normal hepatic function is required tometabolize sodium citrate.

Therefore, trisodium citrate has been used to provide anticoagulation ofblood in the extracorporeal circuit during CRRT. Citrate affectsanticoagulation by binding with calcium and rendering calciumunavailable to the clotting cascade. Since several steps of the clottingcascade are dependent on calcium, the absence of calcium preventsclotting. Once the blood from the extracorporeal circuit is returned tothe patient it mixes with the central venous blood which containscalcium and the anticoagulant effect is neutralized. In other words,citrate when returned to the patient from the extracorporeal circuit isno longer an anticoagulant. Generally, calcium is administered to thepatient on a continuous basis to prevent any depletion of calcium storeswhich may occur as a result of citrate binding with calcium and loss ofcalcium through the extracorporeal circuit.

The prior art has recognized that complications may arise when usingtrisodium citrate as a regional anticoagulant. The toxicities of thisapproach include metabolic alkalosis due to citrate accumulation and itssubsequent metabolism to bicarbonate, and the effects of reducedsystemic ionized calcium. Subjectively the patient may experiencepalpitations, perioral tingling and stomach cramps. Objective featuresof citrate toxicity include myocardial depression, arrhythmias andsystemic alkalosis which may or may not include an anion gap. Propersurveillance of the rate of citrate administration and monitoring andcorrection of systemic ionized calcium may obviate these effects. Sincenormal liver function is required for the metabolism of trisodiumcitrate, patients with liver disease may be prone to developing citratetoxicity and caution must be exercised in treating these patients withcitrate.

Although the use of citrate for regional anticoagulation has been shownto be superior to heparin (4), it often complicates CRRT. A small numberof regional citrate anticoagulation protocols offer high soluteclearance but also require several customized solutions (5,6,7,8,9,10).Customization of solutions, with subsequent adjustments based on ordetermined by patient clinical status, expends pharmacy resources inpreparing the solutions and increases the risk of error in thepreparation of the solutions and their administration (11). Thiscustomization of solutions can vary not only between individualpatients, but can vary as to the same patient based on that patient'schanging clinical status. In addition, if a patient's clinical statuschanges over the course of treatment, previously prepared solutions mayhave to be discarded, thereby increasing the costs of treatment. In2004, two patients receiving CRRT died after potassium chloride, ratherthan sodium chloride, was mistakenly added to a custom-made dialysate(12,13). As the FDA does not presently require batch testing for qualitycontrol, potentially hazardous CRRT solution errors may be unrecognized.In a recent international survey on the management of critically ill ARFpatients, the greatest concerns with CRRT included anticoagulation,dialyzer clotting, nursing workload, lack of standards, and cost (3).

The ideal CRRT protocol should provide volume control, metabolic(acid-base and electrolyte) control, and adequate solute clearance,without significant complications related to bleeding or clotting andshould be versatile to allow for independent adjustment of the aboveparameters. Furthermore, the CRRT protocol should use standardizedsolutions and should not require more than two or three different typesof solutions in order to minimize the strain on the compounding pharmacyand healthcare providers. Finally, the CRRT should ideally run withlittle or no interruption.

The present disclosure provides novel solutions for use with CRRT. Inone embodiment, the CRRT protocol is a continuous venovenoushemodiafiltration (CVVHDF) method. CVVHDF provides both diffusive andconvective solute clearance and easily maintains a filtration fraction<20% at low blood flow rates and high effluent rates, thereby decreasingthe likelihood of filter clotting (14). The present disclosure alsoprovides a simplified set of CRRT solutions for use in CRRT.

Altering the composition of CRRT solutions for each patient proved to becostly, labor-intensive, and error-prone. As a result, we first deviseda simplified citrate protocol using 2% trisodium citrate delivered asreplacement fluid at 250 ml/hr (citrate 17.5 mmol/hr), with astandardized normal saline dialysate delivered at 1000 ml/hr (15).However, this method could not provide higher effluent rates withoutalso causing severe metabolic complications.

In one embodiment, a bicarbonate-based dialysate and a dilute citratesolution used for both anticoagulation and replacement fluid aredisclosed. The citrate solution provides adequate metabolic control, ahigh ultrafiltration rate, and effective regional anticoagulationwithout requiring customization based on the clinical status of anindividual patient.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A shows one embodiment of a schematic diagram of the procedure forCVVHDF CRRT therapy using the 0.67% TSC solution as the replacementfluid solution and Bicarbonate-25 as the dialysate solution.

FIG. 1 B shows one embodiment of a schematic diagram of the procedurefor CVVHDF CRRT therapy using the 0.5% TSC solution as the replacementfluid solution and Bicarbonate-25 as the dialysate solution.

FIG. 2A shows metabolic and electrolyte control for patients treatedwith CVVHDF CRRT therapy as described herein using the 0.67% TSCsolution as the replacement fluid solution and Bicarbonate-25 as thedialysate solution; results are presented as medians and ininterquartile ranges.

FIG. 2B shows metabolic and electrolyte control for patients treatedwith CVVHDF CRRT therapy as described herein using the 0.5% TSC solutionas the replacement fluid solution and Bicarbonate-25 as the dialysatesolution; results are presented as medians and in interquartile ranges.

FIG. 3 shows dialyzer filter survival time (patency) for patientstreated with CVVHDF CRRT therapy as described herein using the 0.67% TSCsolution (dashed line) or 0.5% TSC solution (solid line) as thereplacement fluid solution and Bicarbonate-25 as the dialysate solution;results are presented using Kaplan-Meier analysis.

DETAILED DESCRIPTION

The present disclosure provides standardized solutions of dilute citrateas replacement fluid solution for use in CRRT protocols and furtherprovides methods of using the citrate solution in CRRT protocols. Thepresent disclosure describes a 0.67% trisodium citrate (TSC) solutionand a 0.5% TSC solution as the citrate replacement fluid solution. Thepresent disclosure also provides standardized solutions of dialysate andcalcium for use in CRRT protocols and further provides methods of usingthe dialysate and calcium solutions in combination with the citratereplacement fluid solutions. The standardized solutions and methods ofthe preset disclosure are a practical and economical improvement overcurrently published CRRT protocols incorporating citrate solutions.

The prior art has recognized that citrate solutions could be used inCRRT methods. Prior art CRRT protocols utilizing citrate solutionsrequired solutions customized to meet the needs of the individualpatient in order to address metabolic and electrolyte requirements andoften required further alterations during use as a result of thechanging clinical status of the patient. Table 1 describes the mostrecent CVVHDF CRRT protocols using citrate for regional anticoagulation.As can be seen, the protocols described by Mehta (10), Kutsogiannis (9),Tobe (8) and Cointault (5) require the use of 4 or more solutions duringCRRT. The protocols described by Gabutti (6) and Dorval (7) disclose theuse of 3 solutions; however, it should be noted that the citratesolutions require customization of the potassium (Gabutti) or potassiumand phosphate levels (Dorval) depending on the clinical status of theindividual patients.

The citrate replacement fluid solution, the dialysate solution and thecalcium solution described herein are standardized solutions which donot require modification or customization on a per patient basis orduring use based on the clinical status of the patient. Furthermore, thestandardized replacement fluid, dialysate and calcium solutions are theonly three solutions required in order to implement CRRT methods. Thisis a distinct advantage over many prior art methods which required up to5 distinct solutions (and which were customized based on individualpatient needs). The use of these standardized solutions in CRRT, such asbut not limited to CVVHDF, allow for high solute clearance and superiorregional anticoagulation properties. Therefore, the novel standardizedsolutions disclosed herein do not require customization based on theneeds of an individual patient. Furthermore, the standardized solutionsdisclosed herein do not require alterations during use. The standardizedsolutions achieve metabolic and electrolyte control, as well as aconstant effluent rate, by altering solution flow rates rather than bychanging the composition of the solutions.

Preparation of Standardized Solutions

The present disclosure provides a novel, standardized citratereplacement fluid solution, a standardized dialysate solution and astandardized calcium solution for use in a variety of CRRT protocols.The solutions are described below.

The present disclosure describes a standardized citrate replacementfluid solution and the use of the citrate replacement fluid solution inCRRT methods. The citrate replacement fluid solution comprises fromabout 15 to about 25 mmol/L citrate and from about 130-150 mmol/L sodium(Na+). In one embodiment, the sodium is isotonic (about 140 mmol/L). Twoembodiments of the citrate replacement fluid solution are described: (i)a 0.67% trisodium citrate (TSC) solution; and (ii) a 0.5% TSC solution.In the first embodiment, the 0.67% TSC replacement fluid solutioncomprises 23 mmol/L citrate and 140 mmol/L sodium. The 0.67% TSCsolution was prepared by pooling the following into an empty 3 L bag:2500 mL of 0.45% NaCl, 500 mL of 4% citrate (4% TSC Solution; Baxter,McGraw Park, Ill., U.S.A.), and 6 mL of concentrated NaCl (4 mmol/mL).As would be obvious to one of ordinary skill in the art, alternatemethods of formulation providing alternate volumes may be used. In thesecond embodiment, the 0.5% TSC solution comprises 18 mmol/L citrate and140 mmol/L sodium. The 0.5% citrate solution was prepared by pooling thefollowing into an empty 3 L bag: 2250 mL of 0.45% NaCl, 325 mL of 4%citrate (4% TSC Solution; Baxter, McGraw Park, Ill., U.S.A.), and 15 mLof concentrated NaCl (4 mmol/mL). As would be obvious to one of ordinaryskill in the art, alternate methods of formulation providing alternatevolumes may be used.

The dialysate solution comprises from about 120 to about 145 mmol/Lsodium, from about 110 to about 130 mmol/L chloride (CL-), from about 20to about 35 mmol bicarbonate (HCO₃), from about 2 to about 4 mmol/Lpotassium (K+) and magnesium from about 0.5 to about 0.7 mmol/L. In oneembodiment the dialysate solution comprises 140 mmol/L sodium, 118.5mmol/L chloride, 25 mmol/L bicarbonate, 4.0 mmol/L potassium and 0.58mmol/L magnesium (referred to as Bicarbonate-25). The dialysate solutionwas prepared by pooling the following into an empty 4 L bag: 4000 mL ofSterile Water for injection, 240 mL of Normocarb® (Dialysis SolutionsInc, Toronto, Canada), 36 mL of concentrated NaCl (4 mmol/ml), and 9 mLof concentrated KCl (2 mmol/mL). Normocarb® contains 140 mmol/L,chloride 106.5 mmol/L, bicarbonate 35 mmol/L, and Magnesium 0.75 mmol/L.The calcium solution comprises from about 20 to about 50 mmol/L calcium.In one embodiment, the calcium solution is a calcium gluconate solutionof 38.75 mmol/L prepared by adding 200 mL of 10% calcium gluconatesolution to 1000 mL of 0.9% NaCl. A bicarbonate-based dialysate was usedto offset the citrate removed in the effluent [16,17].

Many methods may be used to formulate solutions described herein. Theforegoing is provided as exemplary only and is not meant to excludeother methods of preparation of the solutions.

Description of CRRT technique

In the embodiment described herein, the CRRT technique was CVVHDF. Inone embodiment, CVVHDF was performed using a COBE Prisma pre-pump M100set with an AN69 dialyzer (effective surface area of 0.9 m²) through adouble lumen 12 French catheter inserted into either the internaljugular, subclavian, or femoral vein. FIGS. 1A and 1B illustrateschematically the CRRT protocol using a 0.67% citrate replacement fluidsolution (FIG. 1A) and a 0.5% citrate replacement fluid solution (FIG.1B). The prepump M100 infusion set is commercially available andconsists of a simple stopcock and extension line that allows a greaterportion of the access line to be diluted by redirecting the citratereplacement fluid solution close to the blood access site and before theblood pump. Such a placement permits anticoagulation of virtually theentire extracorporeal circuit when the citrate replacement solution isdelivered pre-filter. Such a placement also maintains filter patency,extending filter life. The calcium solution was administered through aseparate central venous line (or through the accessory infusion port ofa large bore multi-lumen central venous catheter) Post-filter ionizedcalcium levels were measured from the post-filter blood sample port(blue in color) located on the return line of the Prisma device to guidethe regional citrate dose.

Since the infusion set is routed through the pre-filter replacementfluid port of the Prisma, the citrate replacement fluid solutioninfusion rate is accounted for by the Prisma device in calculations ofnet fluid removal. In the embodiment described, hemodiafiltration wasaccomplished using a blood flow rate of 90-180 mL/min. Other blood flowrates may also be used as is known in the art. In an alternateembodiment, blood flow rates from 50-250 ml/min may be used. The dose ofdialysis obtained using the methods described herein may be calculatedas is know to one of ordinary skill in the art. In one embodiment, aweight based scheme is used to determine the dose of dialysis. Using thePrisma machine, the total effluent rate in mL/hr is equal to the sum ofthe replacement fluid rate (mL/hr), dialysate rate (mL/hr), and fluidremoval rate (mL/hr). In the embodiment described herein, effluent ratesof 35 mL/kg/hr were used and determined by the patient's bodyweight inkilograms at initiation of CVVHDF. Other effluent rates may also be usedas would be obvious to one of ordinary skill in the art. In an alternateembodiment, the effluent rates may be from about 20 to about 50ml/kg/hr. The rate of delivery of the citrate replacement fluid solutionand the dialysate solution may be independently varied from about 500 toabout 3500 ml/hr. In one embodiment, the rate of delivery of the citratereplacement fluid solution and the dialysate solution are 1000 mL/hr.The rate of delivery may be determined by the healthcare provider basedon patient requirements or treatment objectives. The rate of delivery ofthe calcium solution may be varied from about 10 to about 150 mL/hr. Inone embodiment, the rate of delivery of the calcium solution is about 60mL/hr. The rate of delivery may be determined by the healthcare providerbased on patient requirements or treatment objectives.

The rate of delivery of the citrate replacement fluid solution, thedialysate solution and the calcium solution may be titrated from theinitial delivery rate as determined by the healthcare provider based onpatient requirements or treatment objectives. For example, the citratereplacement fluid solution and the dialysate solution may be titratedfrom the initial rate in predetermined increments to maintainpost-filter ionized calcium levels between 0.25-0.5 mmol/L In oneembodiment, the predetermined increments are from about 25 to 200 mL/hr.

The calcium solution may be titrated by in predetermined increments tomaintain systemic ionized calcium levels between 0.9- 1.3 mmol/L. In oneembodiment, the predetermined increments are from about 10 to about 30mL/hr. For example, if systemic ionized calcium levels in the range ofabout 0.8 to 0.9 mmol/L, the rate of delivery of the calcium solutionmay be increased by 10 ml/hr and if the systemic ionized calcium levelsare less than about 0.8 mmol/L, the rate of delivery of the calciumsolution may be increased by 20 mL/hr. If the systemic ionized calciumwere greater than about 1.3 mmol/L, the rate of delivery of the calciumsolution may be decreased by 10 ml/hr increments until a therapeuticlevel was obtained.

In the embodiment described above, the effluent rate (mL/kg/hr) was usedas a surrogate for the dose of dialysis and calculated as follows:Effluent Rate=(Dialysate flow rate (mL/hr)+Replacement fluid flow rate(mL/hr)+Fluid removal rate (mL/hr))/Patient weight (kg)

For example, a 70 kg patient would require a total effluent rate of 2450mL/hr (70 kg×35 mL/kg/hr). Rates for the replacement fluid solution,dialysate solution, and fluid removal would then be adjusted to achievean effluent rate of 2,450 mL/hr. In one embodiment, the replacementfluid solution and dialysate solution rates were set equally atinitiation of CRRT (for example at >1000 ml/hr) and titrated accordingto the metabolic, anticoagulation, and fluid balance requirements of thepatient. The replacement fluid solution and dialysate solution rates mayalso be set to differ from one another. However, the total effluent rateremained constant.

In an alternate embodiment, a non-weight based scheme may be used todetermine the dose of dialysis. In one example of such a scheme, thedelivery rate of replacement fluid solution and dialysate solution maybe set at a constant rate, with changes made to the fluid removal rate.For example, the rates of delivery of the replacement fluid solution andthe dialysate solution may be set as desired (such as from 500 to 3500ml/hr) and, depending on desired volume status to be achieved, the fluidremoval rate may be adjusted.

Monitoring of CRRT Therapy

Serum and post-filter ionized calcium levels are measured to ensure thatpost-filter ionized calcium levels are in the range of 0.25 to 0.5mmol/L and serum ionized calcium levels are in the range of about 0.9 to1.3 mmol/L. Measurements may be taken as determined by the healthcareproviders. In one embodiment, serum and post-filter ionized calciumlevels were measured 1 hour after initiation of CRRT and then every sixhours thereafter. Arterial blood gases (ABGs), serum electrolytes(including but not limited to, magnesium, calcium, and phosphorous),coagulation parameters, and complete blood count are also measured asdetermined by the healthcare providers. In one embodiment, thesecomponents were measured at least daily. Healthcare providers wereinstructed to call for serum pH <7.20 or >7.45, bicarbonate <15 or >35mmol/L, or systemic ionized calcium <0.9 or >1.3 mmol/L. Any changes tothe fluid removal flow rate, citrate replacement fluid solution flowrate, or dialysate solution flow rate resulted in reciprocal adjustmentsto ensure a constant effluent rate of 35 mL/kg/hr. Dialyzer filters werechanged routinely every 72 hours per the manufacturer's recommendations.Monitoring for citrate toxicity was performed as previously described(18).

Statistical Analysis

Results are presented as means, medians, and interquartile ranges.Baseline characteristics and outcome measures were compared using theStudent's t-test or the Wilcoxon rank-sum test for quantitativevariables, and the Pearson Chi-square test or Fisher's Exact test forproportions. Filter survival was compared using Kaplan-Meier survivalstatistics and the log-rank test. A p value <0.05 was consideredstatistically significant.

Methods of Treatment

The present disclosure also describes a method of treating an individualhaving a disease or condition treatable using CRRT and the standardizedsolutions described herein. In one embodiment, the disease or conditionis a renal disease. The renal disease may be, but is not limited to, ARFand CRF. There are a variety of causes that contribute to and/or causeARF or CRF; such causes include, but are not limited to, nephritis, druguse/overdose, surgical intervention, complications arising in prematureinfants and neonatal environments, transplant procedures, burns, trauma,sepsis, shock and multi-organ failure (25). In an alternate embodiment,the disease or condition is not a renal disease and may include, but notbe limited to, drug use/overdose, correction of severe acid baseabnormalities, solute/fluid balance control, congestive heart failure,removal of sepsis mediators or cytokines, cerebral edema states, ARDS,liver support, pancreatitis, and burn management (26). The methods oftreatment comprise identifying an individual in need of such treatmentand administering to such individual the standardized citratereplacement fluid solution and the standardized dialysate solution usinga CRRT protocol. In one embodiment, citrate replacement fluid solutionis the 0.67% TSC solution or the 0.5% TSC solution described herein, thedialysate solution is the Bicarbonate-25 solution and the CRRT protocolis a CVVHDF protocol as described herein where the citrate replacementfluid solution is introduced via the extracorporeal circuit. The citratereplacement fluid solution and the dialysate solution are administeredat rates of about 500 to 3500 mL/hr and the effluent rate is between 20and 45 mL/kg/hr. In one embodiment, the citrate is delivered at a rateof about 10-40 mM/hr.

The present disclosure also provides a method of providing regionalanti-coagulation during a CRRT procedure using the standardizedsolutions described herein. The method of providing anti-coagulationcomprises identifying an individual in need of such anti-coagulation andadministering to such individual the standardized citrate replacementfluid solution and the standardized dialysate solution using a CRRTprotocol. In one embodiment, citrate replacement fluid solution is the0.67% TSC solution or the 0.5% TSC solution described herein, thedialysate solution is the Bicarbonate-25 solution described herein andthe CRRT protocol is a CVVHDF protocol as described herein where thecitrate replacement fluid solution is introduced via the extracorporealcircuit for the prevention of coagulation. The citrate replacement fluidsolution and the dialysate solution are administered at rates of about500 to 3500 mL/hr and the effluent rate is between 20 and 45 mL/kg/hr.In one embodiment, the citrate is delivered at a rate of about 10-40mM/hr.

The present disclosure also provides methods for extending the patencyof a dialysate filter used during a CRRT procedure using thestandardized solutions described herein. The method of extending thepatency of a dialysate filter comprises identifying an individual inneed of CRRT and administering to such individual the standardizedcitrate replacement fluid solution and the standardized dialysatesolution using a CRRT protocol. In one embodiment, citrate replacementfluid solution is the 0.67% TSC solution or the 0.5% TSC solutiondescribed herein, the dialysate solution is the Bicarbonate-25 solutiondescribed herein and the CRRT protocol is a CVVHDF protocol as describedherein where the citrate replacement fluid solution is introduced viathe extracorporeal circuit for the prevention of coagulation. Bypreventing coagulation of the blood in the extracorporeal circuit, thelife of the dialysate filter is extended. In one embodiment, filterpatency was greater than 70% after 72 hours of CRRT. The citratereplacement fluid solution and the dialysate solution are administeredat rates of about 500 to 3500 mL/hr and the effluent rate is between 20and 45 mL/kg/hr. In one embodiment, the citrate is delivered at a rateof about 10-40 mM/hr.

EXAMPLES

The present disclosure provides the following Examples to illustrate theteachings of provided herein. The Examples below are to be understood todescribe the application of certain embodiments of the technologyenabled by the present disclosure and should not be taken as limitingthe present disclosure in any manner. The formulations, methods ofadministration and uses described in the Examples may be modified aswould be known to one of ordinary skill in the art and as set forth inthe present specification. Additional information regarding the methodsused in the present disclosure may be found in (24).

Patient Clinical Characteristics at Initiation of CRRT

Two studies were performed to evaluate the standardized solutions usedin conjunction with a CRRT protocol. In one study, the 0.67% TSCsolution was used as the citrate replacement fluid solution. In a secondstudy, the 0.5% TSC solution was used as the citrate replacement fluidsolution. In both studies the dialysate solution was the Bicarbonate-25solution.

For the studies using the 0.67% TSC solution, 24 consecutive adult ICUpatients with ARF who received CVVHDF from August 2003 to February 2004at the University of Alabama at Birmingham using 0.67% citratereplacement fluid solution and the dialysate solution (Bicarbonate-25)at an effluent rate of 35 mL/kg/hr were prospectively studied. The CRRTprotocols were performed as described herein. For the studies using the0.5% TSC solution, 32 consecutive ICU patients with ARF who receivedCVVHDF from May 2004 to June 2005 using the same protocol except that0.5% citrate replacement fluid solution was used. Patients were eligiblefor inclusion in either group if they were 19 years of age or older andreceived at least 48 hours of CRRT. Data collected upon enrollmentincluded demographics, clinical parameters, Acute Physiology and ChronicHealth Evaluation (APACHE) II score at initiation of CRRT, serumchemistries, arterial blood gas, and coagulation indices. CRRT data,including blood flow rate, dialysate rate, replacement fluid rate, fluidremoval rate, and dialyzer patency, were also recorded daily.

The baseline characteristics of the 24 ICU patients treated with 0.67%citrate replacement fluid solution and the 32 ICU patients treated with0.5% citrate replacement fluid solution are shown in Table 2. Metabolicand CRRT parameters are also summarized. At the initiation of CRRT, 15of 24 patients (56%) in the 0.67% citrate group had sepsis, 13 (54%)were oliguric, 21 (88%) were intubated, and 14 (58%) required pressorsfor hemodynamic support. In the 0.5% citrate group, 13 of 32 patients(41%) had sepsis, 19 (59%) were oliguric, 26 (81%) were intubated, and16 (50%) required pressors. There were no significant differences amongbaseline characteristics between the two groups.

Patient Metabolic and Acid-base Control on CRRT

Acid-base and electrolyte control for the first 10 days of CRRT areshown for both the 0.67% (FIG. 2A) and 0.5% citrate groups (FIG. 2B).The box plot diagrams display median values for pH, pCO2, serumbicarbonate, sodium, and potassium for each day of CRRT, along withinterquartile ranges and extreme values. In the 0.67% citrate group,median pH ranged 7.40- 7.45. Median serum bicarbonate and pCO2 ranged21-27 mmol/L and 30-38 mm Hg, respectively. In the 0.5% citrate group,median pH ranged 7.36- 7.43. Median serum bicarbonate and pCO2 ranged21-25 mmol/L and 31-39 mm Hg, respectively.

Metabolic alkalosis during CRRT occurred more frequently in the 0.67%citrate group, compared to the 0.5% citrate group (p =0.001,Chi-square). Eighteen of 24 patients in the 0.67% citrate group had apH >7.50 (maximum pH 7.62) at some point during CRRT, while only 9 of 32patients in the 0.5% citrate group had a pH >7.50 (maximum pH 7.55).Alkalosis was mitigated by adjusting the rates of the citratereplacement fluid solution and dialysate solution rather than byaltering the composition of the standardized solutions as was done inthe prior art. For example, to correct metabolic alkalosis (pH >7.50) ina patient on CRRT with a dialysate solution flow rate of 1500 ml/hr andcitrate replacement fluid solution flow rate of 1500 ml/hr, thedialysate solution flow rate may be increased a desired amount and thecitrate replacement fluid solution flow rate may be decreased by acorresponding amount to lower the final citrate concentration. Forexample, in the embodiment where the flow rates for the dialysatesolution and the citrate replacement fluid solution are both 1500 mL/hr,the flow rate of the dialysate solution may be increased to 1800 ml/hrand the flow rate for the citrate replacement fluid solution may bedecreased to 1200 ml/hr. As discussed above, the effluent rate remainsconstant as the flow rates underwent corresponding alteration.Decreasing the citrate replacement fluid solution flow rate reducescitrate delivery (and subsequent bicarbonate production) whileincreasing the flow rate of the dialysate solution (where thebicarbonate concentration is 25 mmol/L for the Bicarbonate-25 dialysatesolution) enhances bicarbonate removal, thus lowering the serumbicarbonate levels. Because the dialysate solution is isotonic, problemswith significant hypo- or hypernatremia are avoided. None of thepatients treated with the 0.67% TSC solution and 3% of the patientstreated with the 0.5% TSC solution developed hypernatremia (sodium >150mmol/L), with the maximum sodium of 153 mmol/L. In comparison, using theprior art 2% citrate replacement fluid solution, 23% of treated patientsdeveloped hypernatremia (p <0.01 for both groups, Fisher's Exact test)(19). Potassium levels were normalized using a dialysate potassium bathof 4 mmol/L. Median serum sodium and potassium levels for both the 0.67%and 0.5% TSC solution groups ranged 134-138 mmol/L and 3.6-4.2 mmol/L,respectively. Since bicarbonate-25 dialysate does not containphosphorous, supplementation with phosphorus was sometimes necessary.

Clotting and Ionized Calcium Data on CRRT

In the patients treated with 0.67% TSC solution (n=24), the mean numberof CRRT days per patient was 9.3±8. A total of 111 filters were used.Following initiation of CRRT, 92% of filters were patent at 24 hours,80% at 48 hours, and 69% at 72 hours (FIG. 3). In the patients treatedwith 0.5% TSC solution (n=32), the mean number of CRRT days per patientwas 7.8±8. A total of 137 filters were used. Eighty-nine percent offilters were patent at 24 hours, 82% at 48 hours, and 80% at 72 hours.There was no significant difference in filter patency between groups.This result is a dramatic increase over that observed using prior arttechniques (see Table 1, Circuit Survival Time at 48 hrs).

Systemic ionized calcium levels ranged 0.73-1.45 mmol/L and 0.78-1.54mmol/L for patients treated with the 0.67% TSC solution and 0.5% TSCsolution, respectively. For each abnormal systemic ionized calciumvalue, adjustment to the calcium solution infusion rate per (asdiscussed previously herein) resulted in normalization of the ionizedcalcium level within 1 hour. In the studies presented, there were noinstances of clinically significant hypocalcemia, and furtheradjustments to the infusion rate were minimal once a steady state wasachieved. Most adjustments to the systemic calcium solution infusionoccurred within 24 hours of CRRT initiation. Despite varying the flowrate of the citrate replacement fluid solution from 900-2000 mL/hr,post-filter ionized calcium levels remained <0.5 mmol/L for both groups,except for one instance which corrected by increasing the replacementfluid rate. Post-filter ionized calcium levels ranged 0.17-0.56 mmol/Land 0.16- 0.47 mmol/L for patients treated with the 0.67% TSC solutionand 0.5% TSC solution, respectively. There were no bleeding episodes orinstances of clinically significant citrate toxicity. The maximum totalcalcium to ionized calcium ratio was 2.8 for patients treated with the0.67% TSC solution and 2.7 for patients treated with the 0.5% TSCsolution. Overall, both citrate groups received 80% of prescribed CRRTtherapy as compared to 68% as described by Venkataram et al (20).Transportation for procedures and patient-care issues, rather thansubtherapeutic anticoagulation, mostly contributed to lost treatmenttime.

Discussion

The use of the standardized solutions in CRRT protocols as describedherein provide significant advantages over the prior art. As discussedabove, the CRRT methods described utilize only three standardizedsolutions, thereby greatly reducing the risk of errors in administrationand preparation of the solutions. The reduction of such risk is adrawback in using the methods of the prior art (23). In addition, thesolutions do not require modification/customization of the solutionsbased on the clinical status of the patient and the solutions may beused for an entire patient population (thereby achieving significantcost savings in preparation). Therefore, the standardized solutionsrequire no additional modifications. While some prior art CRRT protocolsutilize commercial solutions, additives are often adjusted according toan individual's metabolic needs, and sometimes customization isnecessary. In contrast, the standardized solutions described herein usestandard compositions for the citrate replacement fluid solution, thedialysate solution (which is now commercially available), and thecalcium solution. Following initiation of CRRT, the composition of eachsolution remains unchanged. This allows for batch preparation ofsolutions, and batch testing, by an admixture pharmacy unit. If CRRT isdiscontinued, unused solutions are available for other patients and notdiscarded.

The use of the standardized solutions in CRRT protocols as describedherein also provides additional benefits.

The use of the citrate replacement solutions in CRRT methodsconsistently provided high solute clearance. As shown in Table 1,dialysis dose rates of 1-2 liters per hour were obtained. Recent datasuggest that a higher dialysis doses lead to improved clinical outcomes.Schiffl et al demonstrated this finding for intermittent hemodialysis,and Ronco et al confirmed this using CVVH (21,2). In one embodiment usedherein, the flow rate of citrate replacement fluid solution anddialysate solution were adjusted to compensate for changes in the fluidremoval rate and thereby maintain an effluent rate of 35 ml/kg/hr(determined in part based on the weight of the patient).

However, other protocols may be used. As not all nephrologists use aweight-based protocol or maintain a constant effluent rate, the citratereplacement fluid solution and the dialysate solution may be initiatedat a set initial flow rate (such as >1000 ml/hr) and adjusted accordingto the discretion of the healthcare provider. As a result, the onlychanges usually required on a daily basis, depending on desired volumestatus, are to the fluid removal rate. Even without a weight-based dose,excellent metabolic control and high solute clearance are achieved.

The electrolytes in the standardized solution are present at physiologicconcentrations, minimizing the risk of metabolic catastrophe in apatient. For instance, even switching the citrate replacement fluidsolution and the dialysate solution will not result in a metaboliccatastrophe as is the case in prior art solutions for use with CRRT.Imagine the metabolic consequences of inadvertently substituting aconcentrated citrate solution (4% TSC) when used as the replacementfluid solution, where the sodium concentration in commercially availablesolutions may be as high as 408 mmol/L (9, 10), for the dialysatesolution, and then increasing the flow rate from 200 mL/hr (a commonrate for 4% TSC replacement fluid solution) to 1000 mL/hr (a common ratefor dialysate solution). Problems may also be encountered when usingconcentrated citrate for anticoagulation and a low-sodium dialysate, asper Mehta's protocol (10). If the citrate replacement fluid solution isomitted, or the low sodium dialysate mistakenly substituted for thecitrate replacement fluid solution, the resulting hyponatremia may befatal. Using the standardized solutions of citrate replacement fluid anddialysate as described herein, any accidental interchanges of thedialysate and citrate replacement fluid solutions, or their respectiverates, results in negligible metabolic consequences due to the dilutecitrate concentration and physiologic content of electrolytes.

When using the 0.5% TSC solution as the citrate replacement fluidsolution, citrate concentration in the range of 2-6 mmol/L was observedwith citrate replacement fluid solution flow rates ranging 1-2 L/hr. Ithas previously been demonstrated that a blood citrate concentration of3-6 mmol/L corresponds to a systemic ionized calcium level <0.35 mmol/L(22). Table 3 illustrates the blood citrate concentration for varyingblood flow and replacement fluid rates using the 0.5% citrate protocol.For ranges in blood flow rates between 100-180 mL/min and replacementfluid rates between 1-2 L/hr, ionized calcium levels are easilymaintained <0.5 mmol/L. Therefore, metabolic complications using thestandardized citrate replacement fluid solution are minimized.

Four of the CRRT protocols incorporating citrate (see Table 1) use athree-way stopcock or Y-connector (5,8,9,10) placed at the end of thearterial limb of the venous access for the citrate infusion. In theseprotocols, the replacement fluid solution is administered as usualthrough the pre-filter replacement fluid port on the dialysis device.Since the stopcock is outside of the CRRT circuit, net fluid removalmeasured by the CRRT device does not include the citrate infusion rate.Thus, the healthcare provider, such as the nursing staff, becomesresponsible for including the amount of citrate infused when net fluidbalance is calculated. As the present disclosure includes citrate in thereplacement fluid solution and the citrate replacement fluid solution isadded at the pre-filter replacement port, the citrate infusioncalculations are accounted for by the dialysis device in calculations ofnet fluid removal. This procedure simplifies the tasks for healthcareproviders and minimizes the risk of error in administration of CRRTtherapy.

Only two protocols use dilute citrate and a total of 3 solutions (6, 7)(see Gabutti and Dorval in Table 1). In 2003, Dorval et al (7)prospectively evaluated 14 patients over 72 hours using a citrateanticoagulation regimen for CVVHDF. While Dorval et al. showed that acitrate containing replacement fluid solution simplified CRRT, only 4 of14 patients actually received a dialysate (and thus CVVHDF), and therest received CVVH (without a dialysate). Potassium and phosphorus wereadded to the replacement fluid as needed, according to patientrequirements, thereby requiring customization of the solutions.Additionally, the ultrafiltration rate was limited to 2 L/hr, due to therisk of citrate toxicity. Gabutti et al (6) evaluated 12 patients usingdilute citrate in both the replacement fluid solution (13.3 mmol/L) anddialysate solution (13.3 mmol/L). In their approach, the compositions ofthe dialysate solution and/or citrate replacement fluid solution weretitrated based on systemic pH again requiring modification of thecomponents of the solutions. While the protocol simplified citrate usewith CVVHDF, it was limited by having to reduce the dialysate andultrafiltration rates at high pH, since both solutions containedcitrate. As a result, some patients with a high pH received onlyreplacement fluid and no dialysate. Furthermore, five patients wereswitched from citrate to heparin for uncertain reasons, and theultrafiltration rate for all patients was limited to 2 L/hr. Finally,filter survival was only 15% at 48 hours.

The remaining citrate protocols shown in Table 1 are more complicated,require additional solutions and mixtures, and have lower filtersurvival rates as compared to CRRT using the standardized solutions ofthe present disclosure. Some patients receiving 0.67% citrate developedmild alkalosis and required adjustment to the replacement fluid solutionflow rate and dialysate solution flow rate for correction. Alkalosis waslater mitigated in the second patient cohort by dilution of the citratereplacement fluid solution to 0.5%. With 0.5% citrate, changes to thereplacement fluid solution flow rate and dialysate solution flow rateonly occurred if the fluid removal rate was altered, in order to keepthe effluent rate at the desired level (in the Examples at 35 mL/kg/hr).Since acid-base status was adequately controlled with the 0.5% solution,further rate adjustments were unnecessary.

Use of the standardized citrate replacement fluid solution and thedialysate solution in CRRT permitted significant cost curtailment in thedelivery of CRRT. This has largely resulted from standardization ofsolutions, less waste, and fewer dialyzer changes for clotting. Thesolution cost for CRRT at the Applicants' center, per patient per day,has declined from $370 to $290 between 1999 and 2005, mainly fromreduced pharmacy costs and the commercial availability of the dialysatesolution (Gambro, Lakewood, CO USA). Furthermore, use of thestandardized citrate replacement fluid solution and the dialysatesolution in CRRT was shown to provide effective metabolic control, highultrafiltration rates, and anticoagulation of the CRRT circuit, withoutincreasing the risk of citrate toxicity. Changes in the composition ofthe citrate replacement fluid solution and the dialysate solution areavoided, thereby containing cost, reducing workload, and minimizingerrors. Furthermore, the risk of adverse patient events, such asbleeding and metabolic catastrophe, is negligible. The standardizedcitrate replacement fluid solution and the dialysate solution are simpleto produce and versatile in that they can be used for the entire patientpopulation. Therefore, the use of the standardized citrate replacementfluid solution and the dialysate solution provides a safe, effective,and practical alternative to the replacement fluid solutions anddialysate solution presently available in the art and represent asignificant step toward the more widespread acceptance of CRRT as themodality of choice for renal replacement in critically ill patients.

REFERENCES

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26. Vanholder R, Biesen W V, Lameire N: What is the renal replacementmethod of first choice for intensive care patients? J Am Soc Nephrol12:S40-S43. 2001 TABLE 1 Comparison of CRRT Protocols Using RegionalCitrate Anticoagulation Repl. Replacement Solution Dialysate BFR*Citrate Solution Citrate Solution Flow Composition Year/Author Pt. #(mL/min) (mM/L) Rate (mM/L) Rate (mM/L) Mehta 1990 18 100 TSC+ 4%Citrate 140-220 mL/hr Pre-filter: Pre-filter: NA 117 140 Na 408(19.6-30.8 mM/hr) NS 0.9% Post- 500 mL/hr Cl 81-121 K 0-4 Mg 1 filter:NS 0.9% Post- Dextrose 0.1% and Variable filter: HCO3 0-40 0.2-1.5 L/hrKutsogiannis  9 100-125 TSC 4% Citrate 140-190 mL/hr Pre-filter:Pre-filter Na 117 Cl 2000 140 Na 408 (19.6-26.6 mM/hr) Na 150.3 Cl 1-1.5L/hr 121.5 K 3-4 Mg 121 HCO3 33.3 0.7 K 3-4 Mg 0.7 Gabutti* 2002 12 150Citrate 13.3 Na 1.5 L/hr See citrate See Citrate 13.3 Na 139.9 Mg 0.75(K (23 mM/hr) solution citrate 139.9 Mg 0.75 as needed) solution (K asneeded) Dorval* 2003 14 125 Hemocitrasol-20 1.25 L/hr See citrate See(Dialysate Na 145 Citrate 20 (25 mM/hr) solution citrate added in onlyGlucose 10 (K solution 27% and PO4 as patients)NS needed) 0.9% Na 154Tobe 2003 15 100 ACD-A ® Citrate 150 mL/hr Pre-filter: NS 0-1 LNormocarb ® 113 Na 224 (17 mM/hr) 0.9% or ½ NS (started Na 140 for HCO335 Cl HCO3 >25) 106.5 Mg 0.75 (K as needed) Cointault* 17 125 ACD-A ®Citrate 250 mL/hr˜ Pre-filter: 1.2 L/hr Hemosol & 2004 113 Na 224 (30mM/hr) Hemosol & Hemosol with Hemosol with Bicarbonate Bicarbonate Na Na144 HCO3 144 HCO3 35 35 Lactate 3 Lactate 3 Mg Mg 0.5 Ca 0.5 Calcium1.75 (mixture 1.75 (mixture of solutions of 2 are varied tosolutions)For adjust Peer Review bicarbonate) Tolwani 2005 32 100-150TSC 0.5% Citrate 1-1.5 L/hr See citrate See Na 140 18 Na 140 (18-27mM/hr) solution citrate K 4 solution HCO3 25 Mg 0.58 (similar solutioncommercially available) Ca Solution Circuit (mM of Survival # D**elemental Calcium Time CRRT Year/Author Rate Ca/L) Rate 48 hrs SolutionsMehta 1990    1 L/hr CaCl 0.8% 40-60 mL/hr 68% 5 Kutsogiannis 1-1.5 L/hrCaCl 40-60 mL/hr 68% 4 2000 0.75% Gabutti* 2002   500 mL/hr 5% CaCl orMean 15% 3 350 mM/L rate: 10 mL/hr or 3.31 mM/hr Dorval* 2003    1 L/hrprn Mg 16 mM/L & 50 mL/hr 50% 3 1% CaCl or 3.5 mM/hr 70 mM/L Tobe 20031-1.5 L/hr CaCl 4 gms 50 mL/hr ˜50%   4 in 1 L D5W Cointault*  1.2 L/hrCaCl 45.6 mM/L 30 mL/hr 41% 4 2004 or 1.37 mM/hr Tolwani 2005   1-2 L/hrCa 60 mL/hr 82% 3 Gluconate or 2.3 mM/hr 38.75 mM/L

TABLE 2 Clinical characteristics of Patients on CVVHDF* (values arepresented as means ± standard deviation) 0.67% Citrate 0.5% CitratePatients N = 24 N = 32 Mean age (years) 63 ± 15 59 ± 16 Male:Female11:13 22:10 Etiology of ARF Sepsis 15 14 Surgery 5 1 Cardiogenic/others4 17 Mean APACHE II** 26 ± 6  26 ± 6  Mean weight (kg) 95 ± 15 90 ± 19Mean BUN (mg/dL)** 91 ± 37 73 ± 35 Mean Creatinine (mg/dL)** 4.2 ± 1.44.3 ± 1.6 Mean pH** 7.33 ± 0.1  7.34 ± 0.09 Mean pCO2 (mmHg)** 33 ± 1134 ± 9  Mean HCO3 (mmol/L)** 19 ± 5  19 ± 5  Mean Na (mmol/L)** 139 ± 7 137 ± 7  Mean K (mmol/L)** 4.5 ± 1.0 4.4 ± 0.8 CRRT characteristics Meandays of CRRT/patient 9.3 ± 8   7.8 ± 8   Mean CRRT effluent rate(mL/kg/hr) 35 35 Mean blood flow (mL/min) 117 ± 12  116 ± 13  Meanreplacement fluid rate (mL/hr) 1200 ± 229  1211 ± 240  Mean fluidremoval rate (mL/hr) 186 ± 57  129 ± 64  Mean dialysate rate (mL/hr)1919 ± 437  1775 ± 542 *For all comparisons between groups, p = NS**At initiation of CRRT

TABLE 3 Blood Citrate Concentration for Varying Blood Flow Rates andCitrate Replacement Fluid Solution Flow Rates Using 0.5% TSC SolutionBlood Flow Rate (ml/ Citrate** (mmol/L) at Citrate (mmol/L) at Citrate(mmol/L) min) RF* 1 L/hr RF 1.5 L/hr at RF 2 L/hr 100 3 4.5 6 120 2.53.75 5 150 2 3 4 180 1.7 2.5 3.3 200 1.5 2.25 3*RF = citrate replacement fluid solution flow rate**A blood concentration of citrate of 3-6 mmol/L corresponds to asystemic ionized calcium concentration less than 0.35 mmol/L

1. A citrate containing replacement fluid solution, said replacementfluid solution consisting essentially of about 15 to about 25 mmol/Lcitrate and from about 130-150 mmol/L sodium.
 2. The replacement fluidsolution of claim 1 consisting essentially of 18 mmol/L citrate and 140mmol/L sodium.
 3. The replacement fluid solution of claim 1 consistingessentially of 23 mmol/L citrate and 140 mmol/L sodium.
 4. A dialysatesolution for use with CRRT, said dialysate solution consistingessentially of about 110 to about 130 mmol/L chloride, about 20 to about35 mmol bicarbonate, from about 2 to about 4 mmol/L potassium and about0.5 to about 0.7 mmol/L magnesium.
 5. The dialysate solution of claim 4consisting essentially of 140 mmol/L sodium, 118.5 mmol/L chloride, 25mmol/L bicarbonate, 4.0 mmol/L potassium and 0.58 mmol/L magnesium.
 6. Acomposition for use in CRRT, said composition comprising a citratereplacement fluid solution and a dialysate solution, where saidreplacement fluid solution and a dialysate solution and said replacementfluid solution comprises about 15 to about 25 mmol/L citrate and about130-150 mmol/L sodium and said dialysate solution comprises about 110 toabout 130 mmol/L chloride, about 20 to about 35 mmol bicarbonate, fromabout 2 to about 4 mmol/L potassium and about 0.5 to about 0.7 mmol/Lmagnesium.
 7. The composition of claim 6 where said replacement fluidsolution comprises 18 mmol/L citrate and 140 mmol/L sodium.
 8. Thecomposition of claim 6 where said replacement fluid solution comprises23 mmol/L citrate and 140 mmol/L sodium.
 9. The composition of claim 6where said dialysate solution comprises 140 mmol/L sodium, 118.5 mmol/Lchloride, 25 mmol/L bicarbonate, 4.0 mmol/L potassium and 0.58 mmol/Lmagnesium.
 10. The composition of claim 6 further comprising a calciumsolution, where said calcium solution is used in combination with saidreplacement fluid solution and said dialysate solution and said calciumsolution comprises about 20 to about 50 mmol/L calcium gluconate. 11.The composition of claim 10 where said calcium solution comprises 38.75mmol/L calcium gluconate.
 12. A method of providing regionalanticoagulation therapy in a patient receiving CRRT, said methodcomprising the step of administering to said patient a standardizedcitrate replacement fluid solution at a first flow rate, saidreplacement fluid solution administered into the extracorporeal circuitof a dialysis unit and prior to a filter of said dialysis unit and saidreplacement fluid solution comprising about 15 to about 25 mmol/Lcitrate and about 130-150 mmol/L sodium.
 13. The method of claim 12where said replacement fluid solution comprises 18 mmol/L citrate and140 mmol/L sodium or 23 mmol/L citrate and 140 mmol/L sodium.
 14. Themethod of claim 12 where said first flow rate is set so as to delivercitrate at a rate of about 18-27 mM/hr.
 15. The method of claim 12 wheresaid first flow rate is about 500 to 3500 mL/hr.
 16. The method of claim12 where said patient maintains a bicarbonate level of between 15 mmol/Land 35 mmol/L, a serum ionized calcium level of between 0.9 mmol/L and1.3 mmol/L and a post-filter ionized calcium level of less than 0.5mmol/L.
 17. The method of claim 12 where said filter maintains a filterpatency after 72 hours of CRRT of at least about 70%.
 18. The method ofclaim 12 where said replacement fluid solution and said dialysatesolution do not require modification based on the clinical status of thepatient.
 19. A method of extending the life of a dialysis filter in apatient receiving CRRT, said method comprising the step of administeringto said patient a standardized citrate replacement fluid solution at afirst flow rate, said replacement fluid solution administered into theextracorporeal circuit of a dialysis unit and prior to a filter of saiddialysis unit and said replacement fluid solution comprising about 15 toabout 25 mmol/L citrate and about 130-150 mmol/L sodium;
 20. The methodof claim 19 where said replacement fluid solution comprises 18 mmol/Lcitrate and 140 mmol/L sodium or 23 mmol/L citrate and 140 mmol/Lsodium.
 21. The method of claim 19 where said first flow rate is set soas to deliver citrate at a rate of about 18-27 mM/hr.
 22. The method ofclaim 19 where said first flow rate is about 500 to 3500 mL/hr.
 23. Themethod of claim 19 where said patient maintains a bicarbonate level ofbetween 15 mmol/L and 35 mmol/L, a serum ionized calcium level ofbetween 0.9 mmol/L and 1.3 mmol/L and a post-filter ionized calciumlevel of less than 0.5 mmol/L.
 24. The method of claim 19 where saidfilter maintains a filter patency after 72 hours of CRRT of at leastabout 70%.
 25. The method of claim 19 where said replacement fluidsolution and said dialysate solution do not require modification basedon the clinical status of the patient.
 26. A method of providingregional anticoagulation therapy in a patient receiving CRRT, saidmethod comprising the steps of: a. administering to said patient astandardized citrate replacement fluid solution at a first flow rate,said replacement fluid solution administered into the extracorporealcircuit of a dialysis unit and prior to a filter of said dialysis unitand said replacement fluid solution comprising about 15 to about 25mmol/L citrate and about 130-150 mmol/L sodium; b. administering to saidpatient a standardized dialysate solution at a second flow rate, saiddialysate solution comprising about 110 to about 130 mmol/L chloride,about 20 to about 35 mmol bicarbonate, from about 2 to about 4 mmol/Lpotassium and about 0.5 to about 0.7 mmol/L magnesium; c. administeringto said patient a standardized calcium solution at a fourth flow rate,said calcium solution comprising about 20 to about 50 mmol/L calciumgluconate; and d. removing fluid from said dialysis unit at a third flowrate, said first, second and third flow rates being independentlyadjusted.
 27. The method of claim 26 where the first, second and thirdflow rates are independently adjusted to maintain a constant effluentrate.
 28. The method of claim 27 where said first, second and third flowrates are independently set so as to maintain an effluent rate of about20-45 mL/kg/hr, where said effluent rate is determined by adding thefirst flow rate, the second flow rate and the third flow rate to obtaina sum and dividing said sum by a body weight of said patient.
 29. Themethod of claim 26 where said first and second flow rates areindependently set at about 500 to about 3500 mL/hr.
 30. The method ofclaim 26 where said replacement fluid solution comprises 18 mmol/Lcitrate and 140 mmol/L sodium or 23 mmol/L citrate and 140 mmol/Lsodium.
 31. The method of claim 26 where said dialysate solutioncomprises 140 mmol/L sodium, 118.5 mmol/L chloride, 25 mmol/Lbicarbonate, 4.0 mmol/L potassium and 0.58 mmol/L magnesium.
 32. Themethod of claim 26 where said first flow rate is set so as to delivercitrate at a rate of about 18-27 mM/hr.
 33. The method of claim 26 wheresaid patient maintains a bicarbonate level of between 15 mmol/L and 35mmol/L, a serum ionized calcium level of between 0.9 mmol/L and 1.3mmol/L and a post-filter ionized calcium level of less than 0.5 mmol/L.34. The method of claim 26 where said filter maintains a filter patencyafter 72 hours of at least about 70%.
 35. The method of claim 26 wheresaid replacement fluid solution and said dialysate solution do notrequire modification based on the clinical status of the patient.